Download Solid Tumour Section Nervous system: Peripheral nerve sheath tumors

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Nervous system: Peripheral nerve sheath tumors
Fredrik Mertens, Ragnhild A. Lothe
Department of Clinical Genetics, Lund University Hospital, 221 85 Lund, Sweden (FM); Department of
Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo, Norway (RAL)
Published in Atlas Database: May 2001
Online updated version : http://AtlasGeneticsOncology.org/Tumors/PeriphNervSheatID5094.html
DOI: 10.4267/2042/37765
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2001 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Pathology
Classification
Schwannomas are encapsulated spindle cell tumors
with distinct Antoni A and B components, hyaline
vessel walls, and nuclear palisading. Tumor cells are
strongly immunopositive for the S-100 protein.
Neurofibromas are unencapsulated tumors composed of
spindle cells dispersed in fibromyxoid stroma. The
proportion of S-100 positive cells is variable.
Perineuriomas may arise in soft tissues or within
nerves, and are composed of cells with elongated
bipolar cytoplasmic processes frequently arranged in
whorls or a storiform pattern. The neoplastic cells
express vimentin and epithelial membrane antigen
(EMA), but are negative for S-100 protein, desmin,
muscle-specific actin, and CD34.
MPNSTs typically are characterized by the presence of
pale spindle cells often arranged in fascicles with
alternating cellular and more myxoid areas. The S-100
protein is expressed in 50-70% of the tumors, and the
majority of cases are immunopositive for TP53. Most
MPNSTs arise from Schwann cells, but the possibility
remains that some arise from nerve sheath cells other
than the Schwann cells, and approximately two-thirds
of all MPNSTs are associated with neurofibromas.
A peripheral nerve sheath tumor (PNST) is a neoplasm
arising from a peripheral nerve or showing nerve sheath
differentiation. PNSTs may be subdivided into benign
and malignant (MPNST) variants. Several distinct
benign subtypes have been recognized, including
schwannoma (neurilemoma, neurinoma), neurofibroma,
and perineurioma.
Clinics and pathology
Etiology
The etiology of PNSTs is usually unknown. However,
several hereditary disorders are known to predispose to
benign
and
malignant
PNSTs,
notably
neurofibromatosis type 1 (NF1) and neurofibromatosis
type 2 (NF2), both of which are inherited in an
autosomal dominant fashion. NF1 (also known as von
Recklinghausen disease) is caused by mutations in the
NF1 gene on chromosome 17 and is characterized by
several phenotypic features including multiple
neurofibromas and MPNSTs. The incidence of MPNST
is in general rare, but half of all cases arise in NF1
patients. NF2, caused by mutations in the NF2 gene on
chromosome 22, predisposes to schwannomas,
predominantly affecting the spine and the intracranial
nerves.
Prognosis
Benign PNSTs rarely recur after surgery. MPNST, on
the other hand, is often a highly aggressive tumor, and
more than 60% of the patients die of the disease.
Epidemiology
Cytogenetics
All ages and both sexes may be affected by PNSTs.
Sporadic MPNSTs are most common between 40 and
50 years of age, while those occurring in the setting of
NF1 are diagnosed some 10 years earlier. In total,
MPNSTs account for 5-10% of all soft tissue sarcomas.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(3)
Cytogenetics Morphological
Schwannomas: Approximately 75 cases with clonal
chromosome aberrations have been reported.
211
Nervous system: Peripheral nerve sheath tumors
Mertens F, Lothe RA
Irrespective of site of origin, these tumors almost
always display a near-diploid karyotype, with loss of
chromosome 22 material, either through loss of the
entire chromosome 22 or through partial deletions of
the long arm, as the most common (about half of the
cases) abnormality. Other recurrent abnormalities
include, in decreasing order of frequency, loss of a sex
chromosome, -17, -15, and +7.
Neurofibromas: Only five cases with clonal
chromosome abnormalities have been reported, and no
recurrent abnormality has been detected among them.
All had, however, near-diploid karyotypes, and one
case displayed monosomy 22.
Perineuriomas: There is a dearth of information on
perineuriomas, but from the few cases that have been
analyzed, it seems as if loss of chromosome 22
sequences is a prominent feature, indicating that they
are pathogenetically related to schwannomas.
MPNSTs: Less than 75 cases with clonal chromosome
aberration have been reported. The majority of cases
displays complex karyotypes, often with a chromosome
number in the tripolid or tetraploid range. No specific
balanced rearrangement has been detected among them.
Frequently involved breakpoints (at least 10% of the
cases) include 1p11, 5p15, 7p22, 9p11, 11q13, 17p11,
17q11, 17q21, 20q13, and 22q11. Frequent (at least
20% of the cases) chromosomal imbalances include
loss of 1p21-p36, 3p21-p23, 5p15, 6q23-q27, 7p22,
9p12-p24, 10p, 11p, 11q13-q25, 12p13, 12q22-q24,
13p, 15p, chromosomes 16 and 17, 19p, 20q13, and
chromosomes 22 and X, and gain of chromosome 7. No
clear difference in karyotypic profile between sporadic
cases and NF1-associated MPNSTs has been detected.
Cytogenetic-morphologic correlations
Schwannoma: No association between karyotypic
features and patient age, tumor size, or site of tumor
origin has been detected.
MPNST: Preliminary data indicate that the presence of
a triploid or tetraploid clone is associated with largesized tumors, high-grade tumors, and shorter overall
survival.
Molecular cytogenetic - clinical correlation MPNST:
One study has reported poor overall patient survival
associated with simultaneous gain of 17q and 7p.
Genes involved and proteins
Note: Molecular genetic findings
Schwannoma: The frequent finding of deletions at 22q
suggests that this chromosome arm harbors one or more
tumor suppressor loci of importance for schwannoma
development. Focussing on the NF2 locus, loss of this
tumor suppressor gene has been demonstrated in one
third to half of all schwannomas investigated. The
importance of this gene in schwannomas is further
supported by the finding of biallelic inactivating
mutations in up to two thirds of the cases.
Neurofibroma: Biallelic inactivation of the NF1 gene in
17q has been demonstrated.
MPNST: The basis for MPNST occurring in the setting
of NF1 is presumed to be biallelic inactivation of the
NF1 gene. Indeed, allelic imbalance at the NF1 locus in
17q is commonly (20-50% of the cases) detected in
sporadic as well as NF1-associated MPNSTs. Due to
the large size of this gene, however, it has been difficult
to identify the mutation in the non-deleted copy in but a
few cases. From studies of neurofibromas in NF1
patients, showing frequent deletion of the wild-type
allele, it is obvious that NF1 inactivation is not
sufficient for malignant transformation. Molecular
genetic investigations aiming at disclosing mechanisms
of importance for tumor progression have revealed that
MPNSTs often display disruption of the RB1 pathway.
Thus, the CDKN2A locus in 9p21 often displays loss of
heterozygosity, and the gene itself is homozygously
deleted or otherwise rendered functionally inactive.
Also the CDKN2B and RB1 tumor suppressor genes
may be inactivated in a subset of MPNSTs.
Alternatively, dominantly acting genes in the RB1
pathway - CDK4, MDM2, and CCND2 - may be
overexpressed or amplified. In a study of 12 MPNSTs,
changes in one or more of these dominantly or
recessively acting genes were found in 11 cases. The
TP53 gene, on the other hand, seems to be biallelically
affected in only a small proportion of MPNSTs.
To be noted
Note: Mouse model
Mice with heterozygous Nf1 germline mutation do not
develop MPNST, and germline homozygosity results in
embryonic lethality. However, mice with heterozygous
germline mutations of both Nf1 and Tp53 develop
MPNST. This animal model and the fact that biallelic
inactivation of TP53 is rare in human MPNST suggest
that other components of the TP53 pathway are targets
for transformation of a neurofibroma into an MPNST.
Cytogenetics Molecular
Schwannoma: Comparative genomic hybridization
(CGH) analysis of a limited number of sporadic and
NF2-associated schwannomas has shown that loss of
22q sequences is the most frequent imbalance.
MPNST: About 50 cases have been investigated by
CGH. In contrast to the imbalance maps derived from
cytogenetic analyses, the CGH data indicate that gain
of distal 17q and loss of 13q14-q21 are frequent
(approximately half of the cases) in MPNST.
Additional frequent changes reported are gain of 5p, 7,
8q and loss of 9p sequences.
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(3)
References
Skuse GR, Kosciolek BA, Rowley PT. Molecular genetic
analysis of tumors in von Recklinghausen neurofibromatosis:
loss of heterozygosity for chromosome 17. Genes
Chromosomes Cancer. 1989 Sep;1(1):36-41
212
Nervous system: Peripheral nerve sheath tumors
Mertens F, Lothe RA
Lothe RA, Slettan A, Saeter G, Brøgger A, Børresen AL,
Nesland JM. Alterations at chromosome 17 loci in peripheral
nerve sheath tumors. J Neuropathol Exp Neurol. 1995
Jan;54(1):65-73
hybridization.
Genes
Aug;25(4):362-9
Cancer.
1999
Schmidt H, Würl P, Taubert H, Meye A, Bache M, Holzhausen
HJ, Hinze R. Genomic imbalances of 7p and 17q in malignant
peripheral nerve sheath tumors are clinically relevant. Genes
Chromosomes Cancer. 1999 Jul;25(3):205-11
Jacoby LB, MacCollin M, Barone R, Ramesh V, Gusella JF.
Frequency and distribution of NF2 mutations in schwannomas.
Genes Chromosomes Cancer. 1996 Sep;17(1):45-55
Vogel KS, Klesse LJ, Velasco-Miguel S, Meyers K, Rushing
EJ, Parada LF. Mouse tumor model for neurofibromatosis type
1. Science. 1999 Dec 10;286(5447):2176-9
Lothe RA, Karhu R, Mandahl N, Mertens F, Saeter G, Heim S,
Borresen-Dale AL, Kallioniemi OP. Gain of 17q24-qter
detected by comparative genomic hybridization in malignant
tumors
from
patients
with
von
Recklinghausen's
neurofibromatosis. Cancer Res. 1996 Oct 15;56(20):4778-81
Antinheimo J, Sallinen SL, Sallinen P, Haapasalo H, Helin H,
Horelli-Kuitunen N, Wessman M, Sainio M, Jääskeläinen J,
Carpén O. Genetic
aberrations in sporadic
and
neurofibromatosis 2 (NF2)-associated schwannomas studied
by comparative genomic hybridization (CGH). Acta Neurochir
(Wien). 2000;142(10):1099-104; discussion 1104-5
Serra E, Puig S, Otero D, Gaona A, Kruyer H, Ars E, Estivill X,
Lázaro C. Confirmation of a double-hit model for the NF1 gene
in benign neurofibromas. Am J Hum Genet. 1997
Sep;61(3):512-9
Mertens F, Dal Cin P, De Wever I, Fletcher CD, Mandahl N,
Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, van Den
Berghe H, Vanni R, Willén H. Cytogenetic characterization of
peripheral nerve sheath tumours: a report of the CHAMP study
group. J Pathol. 2000 Jan;190(1):31-8
Berner JM, Sørlie T, Mertens F, Henriksen J, Saeter G,
Mandahl N, Brøgger A, Myklebost O, Lothe RA. Chromosome
band 9p21 is frequently altered in malignant peripheral nerve
sheath tumors: studies of CDKN2A and other genes of the
pRB pathway. Genes Chromosomes Cancer. 1999
Oct;26(2):151-60
Scheithauer BW, Giannini C, Woodruff JM Perineurioma In:.
Perineurioma. In: Pathology and Genetics of Tumours of the
Nervous System. WHO Classification of Tumours. P Kleihues,
WK Cavenee (Eds.). IARC Press, Lyon, 2000, pp. 169-171.
Cichowski K, Shih TS, Schmitt E, Santiago S, Reilly K,
McLaughlin ME, Bronson RT, Jacks T. Mouse models of tumor
development in neurofibromatosis type 1. Science. 1999 Dec
10;286(5447):2172-6
Lothe RA, Smith-Sørensen B, Hektoen M, Stenwig AE,
Mandahl N, Saeter G, Mertens F. Biallelic inactivation of TP53
rarely contributes to the development of malignant peripheral
nerve sheath tumors. Genes Chromosomes Cancer. 2001
Feb;30(2):202-6
Fletcher CD, Dal Cin P, de Wever I, Mandahl N, Mertens F,
Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, van den
Berghe H, Vanni R, Willén H. Correlation between
clinicopathological features and karyotype in spindle cell
sarcomas. A report of 130 cases from the CHAMP study
group. Am J Pathol. 1999 Jun;154(6):1841-7
This article should be referenced as such:
Mertens F, Lothe RA. Nervous system: Peripheral nerve
sheath tumors. Atlas Genet Cytogenet Oncol Haematol. 2001;
5(3):211-213.
Mechtersheimer G, Otaño-Joos M, Ohl S, Benner A, Lehnert T,
Willeke F, Möller P, Otto HF, Lichter P, Joos S. Analysis of
chromosomal imbalances in sporadic and NF1-associated
peripheral nerve sheath tumors by comparative genomic
Atlas Genet Cytogenet Oncol Haematol. 2001; 5(3)
Chromosomes
213